Proinflammatory Signaling Regulates Hematopoietic Stem Cell Emergence

Espín-Palazón, Raquel; Stachura, David L.; Campbell, Clyde; García‐Moreno, Diana; Cid, Natasha Del; Kim, Albert D.; Candel, Sergio; Meseguer, José; Mulero, Victoriano; Traver, David

doi:10.1016/j.cell.2014.10.031

Cited by 291 publications

(312 citation statements)

References 81 publications

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“…Our results are in agreement with three recent studies showing that the emergence of HSPCs is regulated by an immune/ inflammatory response (42)(43)(44). In one of the studies, Li and colleagues carried out expression profiling of CD31 + Cdh5 + Esam + Ly6a-GFP + Kit + hematopoietic cluster cells (HCCs) compared with endothelial cells (ECs).…”

Section: Transcriptional Profiling Of the Chd1 Mutant Endothelium Revsupporting

confidence: 79%

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Koh

Lizama

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5. Mutant embryos contain normal numbers of E10.5 intraaortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic-specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts.

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Section: Transcriptional Profiling Of the Chd1 Mutant Endothelium Revsupporting

confidence: 79%

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Koh

Lizama

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Neutrophils, and to a less extent macrophages, have been described as the main source of IL-1b and TNF-a (19,43,57), but at the Prim-5 stage macrophages are hardly detected and neutrophils are absent (30,31,56,58). However, we demonstrate that if protective chorion is removed in advance, zebrafish has already developed yet various types of epidermal cells at the surface and inner layer (59) that cope with common stressors (60).…”

Section: Discussionmentioning

confidence: 87%

“…In this work, we have demonstrated a previously unrecognized function for skin keratinocytes as osmotic sensors with a critical role on activating innate immunity and providing protection to bacterial infection in newly hatched zebrafish embryos. Zebrafish has emerged as a good model to study human diseases and immunological mechanisms that are hardly accessible in more classical vertebrate models (6,(40)(41)(42)(43)(44). In our experimental setting, immediately after hatching, keratinocytes recognize a new hyposmotic environment, a mechanism in which the TRPV4 channel plays an important role.…”

Section: Discussionmentioning

confidence: 99%

TRPV4-Mediated Detection of Hyposmotic Stress by Skin Keratinocytes Activates Developmental Immunity

Galindo-Villegas

Montalban-Arques

Liarte

et al. 2016

The Journal of Immunology

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As an organism is exposed to pathogens during very early development, specific defense mechanisms must take effect. In this study, we used a germ-free zebrafish embryo model to show that osmotic stress regulates the activation of immunity and host protection in newly hatched embryos. Mechanistically, skin keratinocytes were responsible for both sensing the hyposmolarity of the aquatic environment and mediating immune effector mechanisms. This occurred through a transient potential receptor vanilloid 4/Ca2+/TGF-β–activated kinase 1/NF-κB signaling pathway. Surprisingly, the genes encoding antimicrobial effectors, which do not have the potential to cause tissue damage, are constitutively expressed during development, independently of both commensal microbes and osmotic stress. Our results reveal that osmotic stress is associated with the induction of developmental immunity in the absence of tissue damage and point out to the embryo skin as the first organ with full capacities to mount an innate immune response.

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“…Larvae were then fixed at 103 hpf to analyze gut morphology or gavaged at 103 hpf to assay barrier function. The previously published and validated tnfr morpholino (5′-CTGCATTGTGACTTACTTATCGCAC-3′; GeneTools) (49,50) was diluted to a concentration of 0.33 mM and 2 nL (total: 5.5 ng per embryo) injected into each embryo. A standard control morpholino (5′-CCTCTTACCTCAGTTACAATTTATA-3′; GeneTools) injected at the same concentration as the tnfa morpholino.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

170

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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Proinflammatory Signaling Regulates Hematopoietic Stem Cell Emergence

Cited by 291 publications

References 81 publications

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

TRPV4-Mediated Detection of Hyposmotic Stress by Skin Keratinocytes Activates Developmental Immunity

Epigenetic control of intestinal barrier function and inflammation in zebrafish

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